Emerging physiologic and genetic data suggest that dysfunction of the pancreatic beta cell is the key determinant of whether an insulin resistant individual will progress to frank hyperglycemia and diabetes. The long-range goal of this applicant is to define the pathways that govern beta cell function and survival in states of health in order to understand how these regulatory circuits are impaired in the pathologic state of Type 2 diabetes mellitus. The sarco-endoplasmic reticulum calcium ATPase or SERCA pump resides in the endoplasmic reticulum membrane and is responsible for maintaining a steep calcium concentration gradient between the cytosol and endoplasmic reticulum. In the beta cell, this gradient plays a key role in regulated insulin secretion and the maintenance of endoplasmic reticulum health and function. Preliminary and published work has revealed that expression of the predominant beta cell isoform, SERCA2, is markedly downregulated in rodent and human models of Type 2 diabetes mellitus. Furthermore, loss of SERCA2 expression leads to profound changes in beta cell secretory function and intracellular calcium flux in response to glucose. Given this background, the overall hypothesis of this proposal is that dysregulation of SERCA2 activity and expression is a key contributor to the beta cell dysfunction and death observed in Type 2 diabetes mellitus. To test this hypothesis, three aims are proposed. Aim 1: elucidate the in vivo role of SERCA2 in beta cell function using two novel mouse models of SERCA2 deficiency. Aim 2: delineate the transcriptional pathways that regulate SERCA2 expression in the pancreatic beta cell under normal conditions and in diabetes. Aim 3: elucidate the contribution of microRNAs in disruption of the SERCA2 gene regulatory network. The successful completion of these aims will precisely define the role of islet beta cell SERCA2 in metabolic and glucose homeostasis and identify the pathways that lead to its transcriptional dysregulation in Type 2 diabetes mellitus. PUBLIC HEALTH RELEVANCE: Type 2 diabetes mellitus affects nearly 1 in 12 Americans and is a leading cause of blindness, kidney failure, amputations, and heart disease. Dysfunction of the insulin producing beta cells in the pancreas plays a prominent role in the development of diabetes. The goal of this project is to define the molecular pathways that lead to beta cell failure in Type 2 diabetes in order to inform the development of novel and improved therapeutic strategies.